Our overall goal is to elucidate the physiologic, genetic, and molecular aspects of two common co-morbid conditions, asthma and nocturnal oxygen desaturation, that increase the incidence rate of pain in sickle cell anemia (SCA). In separate studies, we have shown children with SCA and either asthma or nocturnal desaturation have an increased pajn rate when compared to children without the condition. Also, our group demonstrated that in a murine model of SCA there was significant susceptibility to hypoxia-induced pulmonary vasocongestion when compared to mice without SCA. Unfortunately, we do not know the interrelationship if any, between asthma, nocturnal desaturation and lung disease in SCA. We propose three interrelated projects. The first and second clinical projects will delineate the physiological basis for the association of asthma and nocturnal desaturation with SCA related morbidity. The first project will also obtain DMA and clinical information from 1800 children with SCA participating in the Silent Cerebral Infarct (SIT) Trial. We will perform a case-control study evaluating whether genes associated with asthma increase the risk of pain and ACS episodes. The basic science project will have experiments aimed at defining the molecular mechanisms by which asthma and nocturnal hypoxemia, separately and together, increase lung injury in a transgenic SCA murine model. We will test three global hypotheses: 1) phenotypic and genotypic features of asthma are risk factors for pain and ACS episodes in children with SCA; 2) nocturnal desaturation in children with SCA modifies the effect of asthma on morbidity in SCA; and 3) chronic airway inflammation and nocturnal hypoxia, separately and together, increase HbSS-induced lung injury in a murine SCA model. Taken together, the results of this highly interactive collaboration of clinical and basic scientists will permit new insights into the mechanisms of lung disease, thus providing a strong foundation for targeted therapy for this vulnerable group.